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Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

Mukhopadhyay, Subhankar, Heinz, Eva ORCID:, Porreca, Immacolata, Alasoo, Kaur, Yeung, Amy, Yang, Huei-Ting, Schwerd, Tobias, Forbester, Jessica L, Hale, Christine, Agu, Chukwuma A., Choi, Yoon Ha, Rodrigues, Julia, Capitan, Melania, Jostins-Dean, Luke, Thomas, David C., Travis, Simon, Gaffney, Daniel, Skarnes, William C., Thomson, Nicholas, Uhlig, Holm H., Dougan, Gordon and Powrie, Fiona (2019) 'Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2'. The Journal of Experimental Medicine (JEM), Vol 217, Issue 2, e20180649.

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Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells
(iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL10RB−/− iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS induced
inflammatory cytokines in the presence of exogenous IL-10. IL-10RB−/− Mφs exhibited a striking defect in their ability to kill
Salmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RB
gene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced in
IL-10RB−/− Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls.
Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs.
These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφ
activation and impaired host defense contributing to IBD pathogenesis.

Item Type: Article
Subjects: QU Biochemistry > Cells and Genetics > QU 300 General works
WH Hemic and Lymphatic Systems > Lymphatic System > WH 650 Reticuloendothelial system
WI Digestive System > WI 140 Diseases (General)
Faculty: Department: Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):
Depositing User: Samantha Sheldrake
Date Deposited: 06 Dec 2019 11:04
Last Modified: 06 Dec 2019 11:04


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